Synthesis of pyridinols and intermediate



United rates Thisinvention relates to the synthesis of pyridinols andmore particularly toan improved process for preparing.6-methyl3=pyridinol and 6-hydroxymethyl-3-py1idin0l.

'The objectsofthis .inventionare: (1) the provision of :an improvedprocess .for preparing the known compounds, G-methyl-S-pyridinol and6-hydroxymethyl-3-pyridinol, in high yield and substantially pure state,and (2) the preparation of new intermediates useful in the synthesisthereof.

The process of this invention essentially comprises reductivelyaminating S-hydroxymethyl-furiural to one of the new intermediates ofthis invention, S-hydroxymethylfurfurylamine, by treatment of the formerwith ammonia and hydrogen in the presence of a hydrogenation catalyst,and then either treating the latter with an aqueous acid to form6-methyl-3-pyridinol or acylating the S-hydroxymethyl-furfnrylamine tothe diacyl derivative, dimethoxylating this derivative to its2,5-dimethoxy derivative, and saponifying to obtain6-hydroxymethyl-3-pyridinol.

Both 6-hydroxymethyl-3pyridinol and 6-methyl-3-pyridinol are knowncompounds, with disclosed utility as intermediates in the preparation ofphysiologically active final products. Thus, 6-methyl-3-pyridinol, forexample, can be converted to parasympathomimetically active N-benzyl-3-dimethylcarbamyloxy-6-methylpyridinium bromide by the methoddisclosed by Wuest and Sakal [1. Am. Chem. Soc., 73, 1210-16 (1952)].

The new intermediates of this invention can be represented by thegeneral formula R OHUCHQNHR,

wherein R and R are the same or dilierent and represent hydrogen oracyl, preferably an acyl radical of a hydrocarbon carboxylic acid ofless than ten carbon atoms as exemplified by the lower alkanoic acids(e.g., acetyl and propionyl), the monocyclic aromatic carboxylic acids(e.g., benzoyl and toloyl), and the monocyclic aralkanoic acids (e.g.,phenacetyl and fi-phenylpropionyl).

To prepare the intermediates of this invention 5-hydroxymethylfurfuralis interacted with ammonia and hydrogen in the presence of ahydrogenation catalyst, such as a pyrophoric nickel (e.g., Raneynickel), although other metallic hydrogenation catflyst may be used. Thereaction is preferably conducted under substantially anhydrousconditions by employing liquid ammonia in an inert organic solvent(e.g., a lower alkanol, such as methanol). In order to increase theyield and decrease the time of reaction, the reductive amination isoptimallyconducted at an elevated temperature (e.g., in the range ofabout 50 C. to about 80 C.) under a superatmospheric pressure ofhydrogen.

The 5-hydroxymethyl-furfurylamine, thus formed, can then be acylated inthe usual manner, as by treating With the desired acyl halide or acidanhydride in the presence of an organic base (e.g., pyridine) to yieldthe mono or atent 0 2 ,944,059 Pa t d July 5, 6

"2. diacylated derivative. Thus, if at least two moles of acid anhydride(e.g., acetic anhydride) is employed permole of the furfurylamine, a2,5-diacylate (e.g., 2,5-diacetat) is formed.

The 2 acylamidomethyl-Sfacyloxymethyl-furan (e.g.,2-acetamidomethyl-S-acetoxymethyl-furan) thus formed can then beconverted to 6-hydroxymethyl-3-pyridinol by the general method disclosedby 'C-lauson-Kaas and Lirnborg in U.S. Patent "No. 2,714,576,grantedAugust 2, 1955, byelectrolysis in-methanol and subsequenttreatment with an 'aqueous'base and/or acid.

Alternatively, "the Shydroxymethyl-furfurylamine can be hydrolyzed to6-methyl-3-pyn'dinol by "treatment with dilute-aqueous acid, preferablya dilute aqueous solution of a mineral acid, such as hydrochloric acid,to give'the desired '6 nrethyl-3 pyn'dinol 'in high yield "(-i.e.,yields above The following examples illustrate the invention (alltemperatures =beingin centigrade') EXAMPLE 1 5-hydroxymefhyl-furfurylamine 12.8 g. of S-hydroxymethylfurfural (Haworthet al., J. Chem. Soc, 1944, 667), 30 ml. of methanol, 5 ml. of liquidammonia, and 0.4 g. of Raney nickel are mixed and shaken for one hourunder atmospheres of hydrogen at 65-75". After cooling, the reactionmixture is filtered and the filtrate distilled. The yield is about 9.30g. (72%) of 5 -hydroxymethyl-furfurylamine (pale yellow liquid, B.P.under 0.1 mm. of mercury about 102-105", r15 1.5278).

Analysis.Calcd. for C H O N (127.1): C, 56.7; H, 7.1; N, 11.0. Found: C,56.8;H, 7.4; N, 11.1.

EXAMPLE 2 2-acetamid0methyI-S-acetoxymethyl-furan 1.27 g. ofS-hydroxymethyl-furfurylamine is dissolved in a mixture of 15 ml. ofacetic anhydride and 15 ml. of pyridine. The reaction mixture is leftstanding for two days and then evaporated in vacuo. The residue iscrystallized from ether to yield about 1.93 g. (92%) of 2-acetamidomethyl-S-acetoxymethyl-furan (white crystals, M.P. about65-67").

Analysis.Calcd. for CgH O- N(COCH (211.2): C, 56.9; H, 6.2; N, 6.6; COCH40.8. Found: C, 56.9; H, 6.2; N, 6.3; COCH 38.5.

EXAMPLE 3 6-hydr0xymethyl-.i-pyridinol 1.70 g. (0.0080 mole) of2-acetamidomethyl-S-acetoxymethyl-furan and 200 mg. of ammonium bromideare dissolved in 15 ml. of methanol and the solution is electrolyzedwith the set-up described in U.S. Patent No. 2,714,576 at a temperatureof 21. The electrolysis is conducted for two hours at a current of0.22-0.30 amperes and a potential of 4.6-5.1 volts. After electrolysis,the liquid is poured into a solution of sodium methoxide (from 250 ml.of sodium) in 5 ml. of methanol and the methanol and ammonia evaporatedin a vacuum. 14 ml. of 3 N sodium hydroxide is added and the mixture isheated under reflux for 18 hours and then continuously extracted withether. The ether is evaporated in a vacuum and the remaining mixtureheated for 20 minutes under reflux with 15 ml. of N hydrochloric acid.The mixture is evaporated to dryness in a vacuum and the residue thendissolved in 15 ml. of water. Solid potassium carbonate is added and themixture continuously extracted with ether. The ether extract isevaporated, the residue washed twice with ether and dried. The yield isabout 0.74 g. (74%) of 6-hydroxymethyl-3-pyridinol t j a g 4 (lightbrovvn crystals, about 123-125 It gives a, Sublimation (150 0.05 mm.mercury) gives vvhite 5 red color with aqueous ferric chloride.crystals, M.P. about 169171.

Analysis.Calcd. for C H- O N (125.1): C, 57.6; H, The invention maybeotherwise variously embodied within the scope of the appended claims.Sublimation (125, 0.05 mercury) gives white 6 We claim: crystals, M.P.about1231-25"'. a l 1. Z-acetamidomethyl-S-actoxymethyl-furan.

E V 7 2. A process for preparing fi-methyl-pyridinol, which" 7 g acomprises heating S-hydrOXymethyl-furfuryIamine with a V h t ldf diluteaqueous acid and recovering the 6-methyl-3 -pyridi- 1.27.;g. ofS-hydrbxyniethyl-furfurylamine is dis- 10 1101 Producedsolved in amixture of 60 ml. of hydrochloric acid and 40 I i of water. The reactionmixture is heated for References Cltedm the file of thls i hours. underreflux and then evaporated in a vacuum. r The residue is dissolved in 15of water, solid potas- UNITED STATES PATENTS carbonate-is added and themixturecontinuously ex- 15 2,045,574 Adkins 11111630,.1936 tracted withether. The ether extract is evaporated, the 2,109,159 Willalls Feb, 938.resid ue washed'twice with ether'and dried. The yield is 2,191,029McNally et a1 Feb. 20, 1940 about 0.96 g. (88%) of 6-methyl-3-pyridinol(light 2,191,030 McNally et al Feb. 20,1940 brown crystals, M.P.;about168-170f). It gives a red 7 2,636,882 Dunlop et al. Apr. 28, 1953 colorwith aqueous ferric chloride. 2,672,461 Dunlop et al. Mar. 16, 1954Analysis.Calcd. for C H- 0N (109.1): C, 66.0; H, 2,732,379 Webb Jan. 24,1956 6.5; N, 12.8. Found; C, 66.0; H, 6.5; N, 12.7. 2,734,063 StevensFeb. 7, 1956 V

1. 2-ACETAMIDOMETHYL-5-ACETOXYMETHYL-FURAN.
 2. A PROCESS FOR PREPARING6-METHYL-3-PYRIDINOL, WHICH COMPRISES HEATING5-HYDROXYMETHYL-FURFURYLAMINE WITH A DILUTE AQUEOUS ACID AND RECOVERINGTHE 6-METHYL-3-PYRIDINOL PRODUCED.